Both developmental lead (Pb) exposure and prenatal stress (PS) impact low socioeconomic status communities and target the brain mesocorticolimbic (MESO) system and the hypothalamic-pituitary-adrenal (HPA) axis. Combined Pb and PS in rodents can produce enhanced behavioral toxicity that is related to underlying inter-correlated MESO and HPA axis changes. Preliminary data in Pb+/-PS mice demonstrates hypomethylation of the hippocampal glucocorticoid receptor (GR) gene NR3C1 in both sexes with consequent increased expression in Pb+PS mice only. Pb differentially alters frontal cortex histone acetylation (AcH3K9) levels by gender. Thus MESO GR epigenetic changes may be important mechanisms of Pb+/-PS-induced CNS toxicity. Behavioral experience is a critical determinant of later behavior and brain function, and epigenetic marks can be modified by behavioral experiences. In our studies, positive vs. negative behavioral experience not only differentiated MESO neurotransmitter levels, but also altered the effects of Pb, PS and Pb+PS on neurotransmitter levels. Thus critical to a full understanding of the consequences of Pb+/-PS is a determination of how the nature of behavioral experience might either mitigate/reverse vs. further enhance Pb and PS- associated epigenetic marks, and associated CNS and HPA toxicity. The proposed studies test the hypotheses that: 1) developmental Pb+/-PS induce sex-dependent MESO GR epigenetic changes, including enhanced alterations in response to Pb+PS; 2) different behavioral experiences (i.e., those associated with 'resilience' vs. further pathology) after birth will result in differential profile of epigenetic marks per se that can be related to differences in their ability to mitigate or enhance Pb and/or PS-associated toxicity. These studies will significantly enhance the understanding of CNS epigenetic-behavioral relationships, provide critical information on mechanisms of Pb+/-PS effects, and provide a foundation for establishing behavioral interventions that could assist in mitigating effects of Pb+/-PS effects, two ubiquitous developmental risk factors.